The metabolites of progesterone, desoxycorticosterone, testosterone, androstenedione cortisone and cortisol known as androstanolones and pregnanolones have been the subject of various studies, at least partially elucidating their role in the neurological signal system in mammals. The nomenclature differs in the field and therefore the IUPAC nomenclature will be used throughout this application. The steroids inducing CNS symptoms and disorders of interest in the present application all share a common feature in comprising a 3α-hydroxy group, a 5α or 5β pregnane steroid body, and a ketone on position 20. Examples of such steroids are given in table 1:
TABLE 1Nomenclature of the pregnanolone groupIUPAC - nomenclatureCAS Number3α-hydroxy-5α-pregnan-20-one516-54-13α-hydroxy-5β-pregnan-20-one128-20-13α,21-dihydroxy-5α-pregnan-20-one567-02-23α,21-dihydroxy-5β-pregnan-20-one567-03-33α,11β,17α,21-tetrahydroxy-5β-pregnan-20-one 53-02-13α-11β,17α,21-tetrahydroxy-5α-pregnan-20-one302-91-03α-17α,21-trihydroxy-5α-pregnan-11,20-dione547-77-33α-17α,21-trihydroxy-5β-pregnan-11,20-dione 53-05-4
To the best knowledge of the inventors, all compounds described as novel in the description and examples are previously non-disclosed. Other steroids for the treatment of CNS disorders have however been disclosed, for example in the following documents:
U.S. Pat. No. 5,232,917 (Bolger et al.) and U.S. Pat. Nos. 5,925,630; 5,939,545; 6,143,736; 6,277,838, (Upasani et al.) disclose a number of 3α-hydroxy steroids and some 3β steroids. These patents concern the agonistic modulation of the GABA-A receptor. In other words, the patents are focused on 3α-hydroxy-steroids and their benzodiazepine like effect. All steroids that are modulators of the GABA-A receptor have the common feature of one 3α-hydroxy structure.
WO 99/45931 (Bäckström & Wang) discloses the antagonistic effect of one steroid, namely 33-OH-5α-pregnan-20-one, but is silent about the steroids described in this application.
WO 03/059357 (Bäckström et al.) discloses several 3bets-hydroxy steroids and their antagonistic effect on the GABA-A receptor but is silent about the steroids described in this application.
The antagonistic effects of 3β-OH-5α-pregnan-20-one and other 3β-OH-5α/β pregnan-steroids are disclosed by Wang et al. (Wang M. D., Bäckström T. and Landgren S. (2000) The inhibitory effects of allopregnanolone and pregnanolone on the population spike, evoked in the rat hippocampal CA1 stratum pyramidale in vitro, can be blocked selectively by epiallo-pregnanolone, Acta Physiol Scand 169, 333-341 and Wang M, He Y, Eisenman L N, Fields C, Zeng C M, Mathews J et al., 3β-hydroxypregnane steroids are pregnenolone sulfate-like GABA(A) receptor antagonists, J Neurosci 2002; 22(9):3366-75). In those papers, dose dependent antagonistic effect of 3β-OH-5α/β-pregnan-steroids and sulfatated-steroids are described. However the compounds in the present invention are not mentioned.
The present invention relates to the field of medicinal chemistry and is intended for producing compounds and compositions useful for modulation of the mammal brain excitability via the gamma-aminobutyric acid receptor-chloride ionophore (GABAA-R) complex and other neurotransmitter systems which are, directly or indirectly, correlated to the GABAA-R complex. It has been shown that a variety of steroidal molecules are effective in the modulation and stimulation of GABA signaling, displaying a variety of physiologic effects. The steroids comprising the components 3α-hydroxy-5α/β-pregnan-20-one have been shown to be specific GAB A-A {gamma-aminobutyric acid (A)} receptor enhancers. Due to these properties, these naturally occurring stress- and sex steroids also have adverse effects and cause certain disorders. The adverse effects of the 3α-hydroxy-pregnan-20-one-steroids are the basis for the negative CNS effects induced by these steroids. Examples of the adversive compounds are 3α-hydroxy-5α/β-pregnanolone steroids listed in table 1. Some of these steroids are very potent and have e.g. been shown to have an ability to induce anesthesia at a high pharmacological dose.
As the 3α-hydroxy-pregnane-steroids are endogenously produced and are metabolites of steroid hormones essential for life, their production cannot easily be interrupted. These steroids are produced in high amounts during several days to weeks during acute and chronic stress, the luteal phase of the menstrual cycle and during pregnancy. They are also produced within the brain. Specific blockers are therefore needed as therapy.
It has earlier been shown that certain 3β hydroxy pregnanolone steroids can block the negative brain effect of the aversive stress and sex steroids. A problem with the earlier discovered compounds is that they are easily metabolized in the body at the critical 3 position and that they are difficult to dissolve in water solution.
The direct mechanism at the receptor site has not yet been fully elucidated, due to the structural complexity of the GABAA-R complex. The GABA receptor family includes several subunit compositions, of which some are known to be related to specific functions and disorders in the CNS. One aim of the present invention is thus to find new compounds that are useful in the treatment of anomaly in the excitability of GABA receptors or other neurotransmitters related to GABA receptors, in a manner which can be general or specific for some subunit compositions and functions. Disorders that are caused by the action of endogenously produced 3α-hydroxy-5α steroids or 3α-hydroxy-5β steroids on the GABA-A receptor are well characterized and understood. It is also known that 3α-hydroxy-5α/β-steroids can induce tolerance to themselves and other similar substances after exposure, and that abstinence effects occur at withdrawal of the 3α-hydroxy-5α/β-steroids. This will be further elucidated in the following:
Diseases Caused by 3α-Hydroxy-Pregna(e)n-Steroids
a) Direct Action
It is established that 3α-hydroxy-5α/β-steroids can directly cause inhibition of CNS functions. Examples of disorders and symptoms caused by the direct action of 3α-hydroxy-5α/β-steroids are premenstrual dysphoric disorder, premenstrual syndrome, dementia, Alzheimer's disease, sedation, tiredness, chronic fatigue syndrome, memory disturbance, learning disturbance, disturbance of motor function, fractures, clumsiness, increased appetite and food cravings, obesity, negative mood as tension, irritability, depression, decreased hearing and eye sight, worsening of Petit Mal epilepsy, burn out syndrome.
b) Tolerance
Continuous and long exposure to 3α-hydroxy-5α/β-steroids causes a malfunctioning of the GABA-A receptor system. A tolerance develops and this tolerance is the initial step in a process that ultimately leads to stress sensitivity, concentration difficulties, and loss of impulse control and depression. The action of 3α-hydroxy-5α/β-steroids have been found to be a factor which reinforces drug dependency. This has been the focus of extensive research.
c) Abstinence
A continuous but shorter exposure to 3α-hydroxy-5α/β-steroids results in a withdrawal effect when the exposure is ended. This phenomenon occurs i.e. during menstruation when the production of 3α-hydroxy-5α/β-steroids by the corpus luteum of the ovary is interrupted. This withdrawal phenomenon also occurs after giving birth (post partum) when the 3α-hydroxy-5α/β-steroid production by the placenta is interrupted. The same phenomenon is also noted when a period of stress is ended. As a response to stress, the adrenals have produced 3α-hydroxy-5α/β-steroids. When this production is interrupted, withdrawal symptoms may occur. Examples of conditions that are influenced by this withdrawal/abstinence phenomenon are partial epilepsy where the patient has an epileptic focus in the cerebral cortex where a worsening occurs at the withdrawal period during menstruation. This phenomenon is called “catamenial epilepsy”. Other examples are menstrual related migraine and stress related migraine, mood changes post partum and weekend headache. Abstinence is a sign of an earlier developed tolerance.
In view of the above, it is clear that steroids are important drug candidates. Naturally occurring steroids are however subject to intense metabolism and are therefore usually not suitable for oral administration. Also in other routes of administration the metabolism is high and makes it impossible to use the compounds as medication and treatments as the active parts of the compounds are first destroyed by the metabolism.
A second problem with steroid compounds is that they are difficult to solute in water solutions and therefore difficult to administer in vivo.
These problems and others are solved by compounds according to the present invention.